Crystal modification of torasemide

ABSTRACT

The present invention relates to the characterization of a new crystal modification III of torasemide, to a process for the preparation thereof by the use of controlled acidifying of alkaline solutions of torasemide with inorganic or organic acids with or without addition of a crystal seed, to its use as a raw material for the preparation of the crystal modification I of torasemide and of pharmaceutically acceptable salts of torasemide as well as to pharmaceutical forms containing this new crystal modification III of torasemide.

TECHNICAL FIELD

[0001] The present invention relates to a new crystal modification ofN-(1-methylethylaminocarbonyl)-4-(3-methyl-phenylamino)-3-pyridinesulfonamide (in thefurther text of the application designated by its generic name“torasemide”), particularly to a new crystal modification III oftorasemide, to processes for its preparation, to its use as a rawmaterial for the preparation of the crystal modification I of torasemideand of pharmaceutically acceptable salts of torasemide as well as topharmaceutical forms containing the said new modification III oftorasemide as the active ingredient.

BACKGROUND OF INVENTION

[0002] Torasemide is a compound with interesting pharmacologicalproperties, which is described in DE patent 25 16 025 (Example 71). As adiuretic of Henle's loop it is useful as an agent for preventing heartor heart tissue damages caused by metabolic or ionic abnormalitiesassociated with ischemia, in the treatment of thrombosis, anginapectoris, asthma, hypertension, nephroedema, pulmonary edema, primaryand secondary aldosteronism, Bartter's syndrome, tumours, glaucoma,decreasing of intraocular pressure, acute or chronic bronchitis, in thetreatment of cerebral edema caused by trauma, ischemia, concussion ofthe brain, metastases or epileptic attacks and in the treatment of nasalinfections caused by allergens.

[0003] The ability of a substance to exist in more than one crystal formis defined as polymorphism and these different crystal forms are named“polymorph modifications” or “polymorphs”. In general, polymorphism isaffected by the ability of a molecule of a substance to change itsconformation or to form different intermolecular or intra-molecularinteractions, particularly hydrogen bonds, which is reflected indifferent atom arrangements in the crystal lattices of differentpolymorphs. Polymorphism is found in several organic compounds. Amongmedicaments polymorphism is found in about 70% of barbiturates, 60% ofsulfonamides and 60% of steroids and about 50% of medicaments of thesaid classes are not present on the market in their most stable forms(T. Laird, Chemical Development and Scale-up in the Fine ChemicalIndustry, Principles and Practices, Course Manual, Scientific Update,Wyvern Cottage, 1996).

[0004] The different polymorphs of a substance possess differentenergies of the crystal lattice and, thus, in solid state they showdifferent physical properties such as form, density, melting point,colour, stability, dissolution rate, milling facility, granulation,compacting etc., which in medicaments may affect the possibility of thepreparation of pharmaceutical forms, their stability, dissolution andbioavailability and, consequently, their action.

[0005] Polymorphism of medicaments is the object of studies ofinterdisciplinar expert teams [J. Haleblian, W. McCrone, J. Pharm. Sci.58 (1969) 911; L. Borka, Pharm. Acta Helv. 66 (1991) 16; M.Kuhnert-Brandstätter, Pharmazie 51 (1996) 443; H. G. Brittain, J. Pharm.Sci. 86 (1997) 405; W. H. Streng, DDT 2 (1997) 415; K. Yoshii, Chem.Pharm. Bull. 45 (1997) 338, etc.] since a good knowledge of polymorphismrepresents a precondition for a critical observation of the wholeprocess of medicament development. Thus, at deciding on the productionof a pharmaceutical form in solid state and with regard to the dosesize, stability, dissolution and anticipated action, it is necessary todetermine the existence of all solid state forms (on the market somecomputer programmes can be found, e.g. >>Polymorph<< as a moduleof >>Cerius2<< programme, MSI Inc., USA) and to determine the stability,dissolution and thermodynamic properties of each of them. Only on thebasis of these determinations the appropriate polymorph can be selectedfor the development of pharmaceutical formulations.

[0006] From the great number of such efforts only a few will bementioned. Thus, Gordon et al. (U.S. Pat. No. 4,476,248) protected a newcrystal form of ibuprofen and a process for the preparation thereof;Bunnell et al. (EP 733 635) protected a new crystal form, a process forpreparation thereof and a pharmaceutical formulation of the medicamentolanzapine containing this new crystal form; R. B. Gandhi et al. (EP 749969) protected a new process for the preparation of polymorph form I ofstavudine from a mixture of one or more forms I, II and III; A. Caron etal. (EP 708 103) protected a new crystal form of irbesartane, a processfor the preparation thereof and pharmaceutical formulations containingthis crystal form.

[0007] It is known [Acta Cryst. B34 (1978), 2659-2662 and Acta Cryst.B34 (1978), 1304-1310] that torasemide can exist in two crystalmodifications differing with regard to the parameters of a single cell,which is confirmed by X-ray diffraction on their monocrystals. Bothmodifications are formed simultaneously by the slow evaporation of thesolvent from a solution of torasemide in a mixture petroleumether/ethanol. The modification I with melting point 169° C.crystallizes monoclinically in the space group P 2₁/c (prisms), whilethe modification II with melting point 162° C. crystallizesmonoclinically in the space group P 2/n (foils). Additionally, for themodification I the melting point 169.22° C. is stated in Iyakuhin Kenkyu25 (1994), 734-750.

[0008] According to Example 71 of DE 25 16 025 torasemide in a crystalform with melting point 163-164° C. is obtained.

[0009] In U.S. Pat. No. 4,743,693 and U.S. Pat. No. reissue 34,580 or US4,822,807 and U.S. Pat. No. reissue 34,672 there is disclosed a processfor the preparation of a stable modification I of torasemide from anunstable modification II of torasemide by adding a catalytic amount (1%)of a stable modification I of torasemide into a suspension of theunstable modification in water and stirring the mixture at a temperaturefrom room temperature to 90° C. within 3 hours to 14 days. In U.S. Pat.No. 4,743,693 and US reissue 34,580 it is stated that the stablemodification I of torasemide (monoclinic, space group P2₁/c) has amelting point of 162° C. and the unstable modification II of torasemide(monoclinic, space group P 2/n) has a melting point 169° C., which iscontrary to the statements in Acta Cryst. B34 (1978), 2659-2662, ActaCryst. B34 (1978), 1304-1310 and Iyakuhin Kenkyu 25 (1994), 734-750.

[0010] In the abstract of U.S. Pat. No. 4,822,807 the authors ascribethe melting point 162° C. to the stable polymorph I of torasemide andthe melting point 169° C. to the unstable polymorph II of torasemide,whereas in the claims of the said patent different melting points foreither polymorph are stated, namely for polymorph I the melting point169° C. and for polymorph II the melting point 162° C.

[0011] In the abstract of U.S. Pat. No. reissue 34,672 the authorsascribe the melting point 162° C. to the pure modification I oftorasemide and the melting point 169° C. to the modification II oftorasemide, whereas in the claims the melting point 159-161.5° C. forthe pure polymorph I and the melting point from about 157.5 to about160° C. for the unstable polymorph II are stated.

SUMMARY OF INVENTION

[0012] It has now been surprisingly found that by a controlledacidifying of alkaline solutions of torasemide with inorganic or organicacids with or without addition of a seed crystal at a temperaturebetween 0 and 35° C. within 15 minutes to 25 hours, a new crystalmodification III of torasemide can be prepared.

[0013] By the alkaline solutions of torasemide according to the processof the present invention there are meant an alkaline extract of theoriginal reaction mixture for the synthesis of torasemide, alkalinesolutions of any crystal modification I, II or III of torasemide oralkaline solutions of any mutual mixtures of crystal modifications I, IIor III of torasemide.

[0014] In the process of the present invention for the preparation ofalkaline solutions of torasemide modifications, water solutions oflithium, sodium and potassium hydroxide as well as water solutions ofsodium and potassium carbonate can be used.

[0015] The acidifying of the alkaline torasemide solutions according tothe invention can be performed in inorganic acids such as hydrochloric,sulfuric, phosphoric and nitric acids and in organic acids such asformic, acetic, propionic, oxalic, tartaric, methanesulfonic andp-toluenesulfonic acids.

[0016] As the seed crystal in the processes of the present inventioncrystal powder of one of the isostructure substances, particularlycrystal powder of the crystal modification III of torasemide can beused.

[0017] It has additionally been found that by using the process of thepresent invention no decomposition of torasemide occurs and theimpurities that may be present in the alkaline extract of the originalreaction mixture for the synthesis of torasemide or in modifications I,II or III of torasemide pass, by the present process, into bases, i.e. achemically pure crystal modification III of torasemide is obtained.

[0018] Moreover, it has been found that the new crystal modification IIIof torasemide is stable under normal storage conditions as well as atbeing subjected to increased humidity, which means that it is neithertransformed into the unstable modification II of torasemide nor into thestable modification I of torasemide.

[0019] The new crystal modification III of torasemide has acharacteristic X-ray powder pattern obtained by X-ray diffraction on apowder sample of the new crystal modification III of torasemide in theinstrument PHILIPS PW3710 under Cu X-rays [λ (CuKα₁)=1.54046 Å andλ(CuKα₂)=1.54439 Å]. Thus obtained characteristic spacings betweenlattice planes designated by )>d(< and expressed in Angström units andtheir corresponding characteristic relative intensities designated by>>I/I₀<< and expressed in % are represented in Table 1. TABLE 1Modification III d(Å) I/I₀ (%) 15.3898 2.8 12.5973 5.4 11.4565 5.89.7973 69.8 9.5493 76.6 8.6802 28.5 8.2371 100.0 7.6351 10.2 7.3356 13.06.9759 1.2 6.5351 10.0 6.3240 7.9 6.1985 4.5 5.9521 0.6 5.6237 24.45.5623 29.7 5.4040 19.6 5.1119 10.3 4.8738 22.7 4.7865 46.9 4.6986 45.74.5985 17.9 4.4602 24.7 4.3405 90.0 4.2552 20.7 4.1829 19.9 4.0768 19.93.9377 47.1 3.8659 29.3 3.8429 35.3 3.7801 42.8 3.7248 11.9 3.6239 31.73.5556 20.5 3.4825 7.8 3.4130 8.1 3.3055 15.5 3.2298 8.2 3.1786 10.73.1278 5.6 3.0699 7.1 3.0078 17.5 2.9549 5.1 2.9056 4.3 2.8541 1.82.7686 13.9 2.6988 5.7 2.6610 6.3 2.6293 7.3 2.5549 3.7 2.5236 2.02.4485 5.3 2.4161 6.7 2.3671 2.0 2.3133 3.6 2.2788 7.6 2.2312 3.4 2.18526.2 2.1468 3.0 2.0957 4.7 2.0617 4.1 2.0273 3.3 1.9896 3.1 1.9688 4.11.9274 2.6 1.8853 2.7 1.7931 2.1 1.7449 1.0 1.7169 1.8 1.6512 1.0 1.61220.8 1.5601 0.8 1.5320 0.3 1.5057 0.5 1.4521 0.3 1.3773 0.6

[0020] In addition, by recording the monocrystal of the new crystalmodification III of torasemide in four circle PHILIPS PW 1100/Stoe&Ciediffractometer under Mo X-rays [λ(MoKα)=0.71073 Å] there were obtainedthe basic crystallographic data for a single cell, which show incomparison with the literature data for crystal modifications I and IIof torasemide [Acta Cryst. B34 (1978), 2659-2662 and Acta Cryst. B34(1978), 1304-1310] that this is an absolutely new crystal modificationIII of torasemide.

[0021] The basic crystallographic data (diffraction on monocrystal) formodifications I, II and the new crystal modification III of torasemideare represented in Table 2. TABLE 2 Crystal modification of torasemideParameter I II III crystal composition monoclinic monoclinic monoclinicspace group P 2₁/c P 2/n P 2₁/c a (Å) 13.308 20.446 11.430 b (Å) 8.22311.615 19.090 c (Å) 31.970 16.877 16.695 β (°) 107.01 108.90 93.903 V(Å³) 3345.5 3791.9 3634.7 Z 4 × 2 4 × 2 4 × 2

[0022] The new crystal modification III of torasemide prepared accordingto the process of the present invention can be transformed by the use ofcommon processes to the crystal modification I of torasemide, i.e. itcan be used as a starting material for the preparation of known crystalmodification I of torasemide.

[0023] The new crystal modification III of torasemide prepared accordingto the invention can be transformed to pharmaceutically acceptable saltsof torasemide by the use of common processes.

[0024] The dissolution profile (U.S. Pat. No. 23) of the new crystalmodification III of toresamide in water and in artificial intestinaljuice in comparison to dissolution profiles of known crystalmodifications I and II of toresamide, in the same fluids, shows asignificant difference.

[0025] IDR (Intrinsic Dissolution Rate) of the new crystal modificationIII of torasemide in a model of artifical gastric juice exceeds 1 mgcm⁻²min⁻¹, which indicates a potential good bioavailability.

[0026] The new crystal modification III of torasemide is preparedaccording to the process of the present invention in the form of aflowable crystal powder of a prismatic habitude, which exhibitsflowability, i.e. it comes in a “free flow” form, wherein no staticcharge accumulation occurs.

[0027] The new crystal modification III of torasemide prepared accordingto the process of the present invention can be used as a suitabletorasemide form as a diuretic as well as an agent for preventing heartor heart tissue damages caused by metabolic or ionic abnormalitiesassociated with ischemia, in the treatment of thrombosis, anginapectoris, asthma, hypertension, nephroedema, pulmonary edema, primaryand secondary aldosteronism, Bartter's syndrome, tumours, glaucoma, fordecreasing intraocular pressure, acute or chronic bronchitis, in thetreatment of cerebral edema caused by trauma, ischemia, concussion ofthe brain, metastases or epileptic attacks and in the treatment of nasalinfections caused by allergens. The present invention also relates topharmaceutical forms such as tablets containing the new crystalmodification III of torasemide as the active ingredient combined withone or more pharmaceutically acceptable additives such as sugar, starch,starch derivatives, cellulose, cellulose derivatives, mould releaseagents, and antiadhesive agents and possibly agents for flowabilityregulation. When using the new crystal modification III of torasemidefor the preparation of pharmaceutical forms, also process steps takingplace in water, e.g. granulation, can be used.

[0028] The starting materials for the process of the present inventioni.e. the alkaline extract of the original reaction mixture fortorasemide synthesis can be prepared according to DE 25 16 025, whereasthe modifications I and II of torasemide can be prepared according toActa Cryst. B34 (1978), 1304-1310.

SUMMARY OF DRAWINGS

[0029]FIG. 1 is a graph of dissolution tests of torasemide in water.

[0030]FIG. 2 is a graph of dissolution tests of torasemide in artificialintestinal juice.

BEST AND VARIOUS MODES FOR CARRYING OUT INVENTION

[0031] The present invention is illustrated but in no way limited by thefollowing Examples.

EXAMPLE 1

[0032] Technically pure new crystal modification III of torasemide:

[0033] The original alkaline extract of the reaction mixture fortorasemide synthesis (1000 ml) prepared according to DE 25 16 025 wasacidified with 10% aqueous acetic acid solution under the addition of1.4 g of a crystal modification III of torasemide. The suspension wasstirred at room temperature for 90 minutes. The crystals were suckedoff, washed with 1 litre of demineralized water and dried in a vacuumdryer at 50° C. for 3 hours. There were obtained 125 g of a crystalmodification III of torasemide, m.p. 162-165° C.

[0034] The X-ray powder pattern of the thus obtained sample correspondedto the new crystal modification III of torasemide. The content oftorasemide according to the HPLC method was >99%.

EXAMPLE 2

[0035] The crystal modification III of torasemide (1000 g) preparedaccording to the Example 1 was dissolved in a 10-fold amount of 5%aqueous potassium hydroxide solution and at the temperature of 20° C.the obtained solution was acidified with 5% aqueous hydrochloric acidsolution under the addition of 10 g of a crystal modification III oftorasemide. The suspension was stirred at 20° C. for 120 minutes. Thecrystals were sucked off, washed with 4 litres of demineralized waterand dried in a vacuum dryer at 50° C. for 3 hours. There were obtained961 g of a modification III of torasemide, m.p. 165° C.

[0036] The X-ray powder pattern of the thus obtained sample correspondedto the crystal modification III of torasemide. The content of torasemideaccording to the HPLC method was >99.5%, i.e. it corresponded tochemically pure torasermide.

EXAMPLE 3

[0037] The crystal modification I of torasemide (1.00 g) preparedaccording to Acta Cryst. B34 (1978), 1304-1310 was dissolved in a10-fold amount of 10% aqueous sodium carbonate solution and at thetemperature of 15° C. the obtained solution was acidified with 5%aqueous sulfuric acid solution under the addition of 0.10 g of themodification III of torasemide. The suspension was stirred at 15° C. for120 minutes. The crystals were sucked off, washed with 4 ml ofdemineralized water and dried in a vacuum dryer at 50° C. for 3 hours.There were obtained 0.95 g of a crystal modification III of torasemide,m.p. 165-166° C.

[0038] The X-ray powder pattern of the thus obtained sample correspondedto the crystal modification III of torasemide. The content of torasemideaccording to the HPLC method was >99.5%, i.e. it corresponded tochemically pure torasemide.

EXAMPLE 4

[0039] The crystal modification II of torasemide (1.00 g) preparedaccording to Acta Cryst. B34 (1978), 1304-1310 was dissolved in a10-fold amount of 10% aqueous pottasium carbonate solution and then atthe temperature of 15° C. the obtained solution was acidified with 5%aqueous ritric acid solution under the addition of 0.10 g of amodification III of torasemide. The suspension was stirred at 15° C. for120 minutes. The crystals were sucked off, washed with 4 ml ofdemineralized water and dried in a vacuum dryer at 50° C. for 3 hours.There were obtained 0.96 g of a crystal modification III of torasemide,m.p. 164-166° C.

[0040] The X-ray powder pattern of the thus obtained sample correspondedto the crystal modification III of torasemide. The content of torasemideaccording to the HPLC method was >99.5%, i.e.it corresponded tochemically pure torasemide.

EXAMPLE 5

[0041] A mixture of crystal modifications I and II of torasemide (1.00g) prepared according to Acta Cryst. B34 (1978), 1304-1310 was dissolvedin a 10-fold amount of 10% aqueous lithium hydroxide solution and thenat room temperature the obtained solution was acidified with 5% aqueousphosphoric acid solution under the addition of 0.10 g of a modificationIII of torasemide. The suspension was stirred at 15° C. for 240 minutes.The crystals were sucked off, washed with 4 ml of demineralized waterand dried in a vacuum dryer at 50° C. for 3 hours. There were obtained0.97 g of a crystal modification III of torasemide, m.p. 165-166° C.

[0042] The X-ray powder pattern of the thus obtained sample correspondedto the crystal modification III of torasemide. The content of torasemideaccording to the HPLC method was >99.5%, i.e. it corresponded tochemically pure torasemide.

EXAMPLE 6

[0043] A mixture of crystal modifications I and III of torasemide (1.00g) prepared according to Acta Cryst. B34 (1978), 1304-1310 and Example 1was dissolved in a 10-fold amount of 5% aqueous potassium hydroxidesolution and then at the temperature of 30° C. the obtained solution wasacidified with 10% aqueous tartaric acid solution under the addition of0.10 g of a modification III of torasemide. The suspension was stirredat 30° C. for 180 minutes. The crystals were sucked off, washed with 4ml of demineralized water and dried in a vacuum dryer at 50° C. for 3hours. There were obtained 0.93 g of a crystal modification III oftorasemide, m.p. 164-166° C.

[0044] The X-ray powder pattern of the thus obtained sample correspondedto the crystal modification III of torasemide. The content of torasemideaccording to the HPLC method was >99.5%, i.e. it corresponded tochemically pure torasemide.

EXAMPLE 7

[0045] A mixture of crystal modifications II and III of torasemide (1.00g) prepared according to Acta Cryst. B34 (1978), 1304-1310 and Example 1was dissolved in a 10-fold amount of 5% aqueous sodium hydroxidesolution and then at the temperature of 35° C. the obtained solution wasacidified with 5% aqueous propionic acid solution under the addition of0.10 g of a modification III of torasemide. The suspension was stirredat 35° C. for 90 minutes. The crystals were sucked off, washed with 4 mlof demineralized water and dried in a vacuum dryer at 50° C. for 3hours. There were obtained 0.87 g of a crystal modification III oftorasemide, m.p. 165° C.

[0046] The X-ray powder pattern of the thus obtained sample correspondedto the crystal modification III of torasemide. The content of torasemideaccording to the HPLC method was >99.5%, i.e. it corresponded tochemically pure torasemide.

EXAMPLE 8

[0047] A mixture of crystal modifications I, II and III of torasemide(1.00 g) prepared according to Acta Cryst. B34 (1978), 1304-1310 andExample 1 was dissolved in a 10-fold amount of 10% aqueous sodiumcarbonate solution and then at the temperature of 25° C. the obtainedsolution was acidified with 5% aqueous p-toluenesulfonic acid solutionunder the addition of 0.10 g of a modification. III of torasemide. Thesuspension was stirred at 25° C. for 60 minutes. The crystals weresucked off, washed with 4 ml of demineralized water and dried in avacuum dryer at 50° C. for 3 hours. There were obtained 0.93 g of acrystal modification III of torasemide, m.p. 164-166° C.

[0048] The X-ray powder pattern of the thus obtained sample correspondedto the crystal modification III of torasemide. The content of torasemideaccording to the HPLC method was >99.5%, i.e. it corresponded tochemically pure torasemide.

EXAMPLE 9

[0049] A crystal modification I of torasemide (1.00 g) preparedaccording to Acta Cryst. B34 (1978), 1304-1310 was dissolved in a10-fold amount of 10% aqueous potassium carbonate solution and then atthe temperature of 15° C. the obtained solution was stepwise acidifiedwith 10% aqueous acetic acid solution under the simultaneous stepwiselowering of the temperature of the mixture to 0° C. At this temperaturethe suspension was stirred for 25 hours. The crystals were sucked off,washed with 4 ml of demineralized water and dried in a vacuum dryer at50° C. for 3 hours. There were obtained 0.94 g of a crystal modificationIII of torasemide, m.p. 164-166° C.

[0050] The X-ray powder pattern of the thus obtained sample correspondedto the crystal modification III of torasemide. The content of torasemideaccording to the HPLC method was >99.5%, i.e. it corresponded tochemically pure torasemide.

EXAMPLE 10

[0051] Production of 2.5 mg tablets:

[0052] Torasemide of the crystal modification III was mixed with lactoseand corn starch in a common manner, granulated with water, dried andsieved (granulate 1). Colloidal silicon dioxide and magnesium stearatewere mixed, sieved and admixed into granulate 1. This mixture was thentabletized in a common manner. For the production of 100 000 tablets thefollowing is required: torasemide-crystal modification III  0.25 kglactose (Lactose Extra Fine Crystal HMS ®)  6.05 kg corn starch(Starch ®)  1.60 kg colloidal silicon dioxide (Aerosil 200 ®) 60.00 gmagnesium stearate 40.00 g redistilled water  1.20 kg

EXAMPLE 11

[0053] Production of 100 mg tablets:

[0054] Torasemide of crystal modification III was mixed with lactose andcorn starch and a part of magnesium stearate in a common manner. Themixture was compressed and sieved to obtain the desired grain size anddistribution of grain size (granulate 1). Colloidal silicon dioxide andmagnesium stearate were mixed, sieved and admixed into granulate 1. Thismixture was then tabletized in a common manner. For the production of100 000 tablets the following is required: torasemide-crystalmodification III 10.0 kg lactose (Lactose Extra Fine Crystal HMS ®  2.0kg corn starch (Starch ®)  7.7 kg colloidal silicon dioxide (Aerosil200 ®)  0.2 kg magnesium stearate  0.1 kg

EXAMPLE 12

[0055] The microcrystallinic modifications I, II and III of torasemideprepared according to Acta Crst. B34 (1978), 1304-1310 and Example 1were subjected to dissolution testing in water, and in artificialintestinal juice, at 37° C. (U.S. Pat. No. 23), and results are reportedin tables 3 and 4. TABLE 3 Dissolution test of torasemide in water (USP23) (37° C., 50 rpm., 1000 ml) % Dissolved torasemide Minutes Mod. IMod. II Mod. III  0 0 0 0 10 6.7 15.1 15.6 20 13.0 27.8 28.1 30 18.539.2 37.7 40 23.5 48.8 43.6 50 28.5 56.3 48.5 60 32.8 65.1 51.1

[0056] TABLE 4 Dissolution test of torasemide in artificial intestinaljuice (USP 23) (37° C., 50 rpm, pH 7.5, 1000 ml) % Dissolved torasemideMinutes Mod. I Mod. II Mod. III  0 0 0 0 10 29.4 73.3 41.0 20 40.5 92.659.8 30 48.4 95.5 70.2 40 54.2 96.8 77.6 50 59.2 96.3 82.5 60 65.0 98.288.7

[0057] The results reported in Table 3 were plotted in the FIG. 1. Theresults reported in Table 4 were plotted in FIG. 2.

1. New crystal modification III of torasemide, characterized in that thecharacteristic X-ray powder pattern of its sample is represented by thefollowing spacings between lattice planes: New crystal modification IIIof torasemide d(Å) 15.3898 12.5973 11.4565 9.7973 9.5493 8.6802 8.23717.6351 7.3356 6.9759 6.5351 6.3240 6.1985 5.9521 5.6237 5.5623 5.40405.1119 4.8738 4.7865 4.6986 4.5985 4.4602 4.3405 4.2552 4.1829 4.07683.9377 3.8659 3.8429 3.7801 3.7248 3.6239 3.5556 3.4825 3.4130 3.30553.2298 3.1786 3.1278 3.0699 3.0078 2.9549 2.9056 2.8541 2.7686 2.69882.6610 2.6293 2.5549 2.5236 2.4485 2.4161 2.3671 2.3133 2.2788 2.23122.1852 2.1468 2.0957 2.0617 2.0273 1.9896 1.9688 1.9274 1.8853 1.79311.7449 1.7169 1.6512 1.6122 1.5601 1.5320 1.5057 1.4521 1.3773


2. New crystal modification III of torasemide according to claim 1,characterized in that in accordance with X-ray diffraction on its samplemonocrystal it is represented by the following basis crystallographicdata: New crystal modification of Parameter torasemide crystalcomposition monoclinic space group P 2₁/c a (Å) 11.430 b (Å) 19.090 c(Å) 16.695 β (°) 93.903 V (Å³) 3634.7 Z 4 × 2


3. New crystal modification III of torasemide according to claim 1,characterized in that it is chemically pure.
 4. New crystal modificationIII of torasemide according to claim 1, characterized in that it doesnot contain water.
 5. New crystal modification III of torasemideaccording to claim 1, characterized in that it does not contain asolvent.
 6. Process for the preparation of a new crystal modificationIII of torasemide according to claim 1, characterized in that analkaline torasemide solution is subjected to controlled acidifying withinorganic or organic acids with or without addition of a seed crystal ata temperature between 0° C. to 35° C. within 15 minutes to 25 hours. 7.Process for the preparation of a new crystal modification III oftorasemide according to claim 6, characterized in that as the alkalinetorasemide solution an alkaline extract of the original reaction mixturefor the synthesis of torasemide is used.
 8. Process for the preparationof a new crystal modification III of torasemide according to claim 6,characterized in that as the alkaline torasemide solution an alkalinesolution of any crystal modification I, II or III of torasemide or analkaline solution of any mutual mixture of crystal modifications I, IIor III of torasemide is used.
 9. Process according to claim 6,characterized in that for the preparation of the alkaline torasemidesolutions water solutions of lithium, sodium and potassium hydroxide andwater solutions of sodium and potassium carbonate are used.
 10. Processaccording to claim 6, characterized in that for acidifying inorganicacids such as hydrochloric, sulfuric, phosphoric or nitric acid ororganic acids such as formic, acetic, propionic, oxalic, tartaric,methanesulfonic or p-toluensulfonic acid are used.
 11. Process accordingto claim 6, characterized in that as the crystal seed crystal powder ofone of the isocrystallinic substances is used, most preferably crystalpowder of a crystal modification III of torasemide.
 12. A new crystalmodification III of torasemide according to claim 1, characterized inthat it is used as a raw material for the preparation of crystalmodification I of torasemide.
 13. A new crystal modification III oftorasemide according to claim 1, characterized in that it is used as araw material for the preparation of pharmaceutically acceptable salts oftorasemide.
 14. A new crystal modification III of torasemide accordingto claim 1, characterized in that it is used as a form of torasemide asa diuretic, as an agent for preventing heart or heart tissue damagescaused by metabolic or ionic abnormalities associated with ischemia, inthe treatment of thrombosis, angina pectoris, asthma, hypertension,nephroedema, pulmonary edema, primary and secondary aldosteronism,Bartter's syndrome, tumours, glaucoma, for decreasing intraocularpressure, acute or chronic bronchitis, in the treatment of cerebraledema caused by trauma, ischemia, concussion of the brain, metastases orepileptic attacks and in the treatment of nasal infections caused byallergens.
 15. A pharmaceutical form, characterized in that it containsas the active ingredient the new crystal modification III of torasemideaccording to claim 1 combined for this purpose with pharmaceuticallyacceptable one or more carriers, additives or diluents.
 16. Apharmaceutical form according to claim 15, characterized in that it isin tablet form.